Limb-girdle muscular dystrophy (LGMD) is a class of muscular dystrophies characterized by progressive proximal skeletal muscle weakness and a distinct pattern of abnormalities on muscle biopsy. However, the LGMDs have a number of genetic causes and an array of different clinical outcomes. The quality of life has improved significantly for affected individuals, due primarily to supportive treatment, but currently no cur is available. A significant proportion of individuals affected by LGMD do not have mutations in the known genes, indicating that several causative genes for LGMD have yet to be discovered. The search for these genes has until recently been difficult, as many affected individuals represent sporadic cases, and thus potential LOD scores would be low and linkage scans would yield many candidates genes. The rapid advances in next generation sequencing technology is lowering these barriers, and will change many assumptions about genetic diagnosis in the research and clinical realms. Next generation sequencing will enable researchers and clinicians to identify causative mutations in sporadic cases as well as larger families that yield broad, low, or multiple linkage peaks with an abundance of candidate genes. The investigator along with his laboratory and his collaborators, have enrolled many kindreds affected by LGMD. Several of these families have a high likelihood of yielding novel causative genes. This combined approach, using both linkage analysis and next generation sequencing, is a powerful one that will broaden our knowledge of the muscular dystrophies. Next generation sequencing is already being applied in clinical settings, and a better understanding of the strengths and limitations of this technology will be important to grasp to make the greatest use of its potential.